Evaluation of cytotoxic activity of titanocene difluorides and determination of their mechanism of action in ovarian cancer cells

Summary

Background Ovarian cancer is the seventh-most common cancer amongst women and the most deadly gynecologic cancer. Cisplatin based drugs are used in first line therapy, but resistance represents a major obstacle for successful treatment. In this study, we investigated the anticancer effects and mechanism of action of three titanocene difluorides, two bearing a pendant carbohydrate moiety (α-d-ribofuranos-5-yl) on their periphery and one without any substitution. Results The efficacy of these compounds on ovarian cancer cell lines was evaluated in relation to their particular chemical structure and compared with cisplatin as the most common treatment modality for this type of cancer. The typical mechanism of cisplatin action involves DNA damage, activation of p53 protein and induction of cell death, as previously described for titanium ions. Nevertheless, our data indicate that the effect of titanocene difluoride derivatives is mediated via the endoplasmic reticulum stress pathway and autophagy. Conclusion We anticipate that the presence of substituents on cyclopentadienyl ring(s) might play an important role in modulation of the activity of particular compounds. Titanocene difluorides exert comparable cytotoxic activity as cisplatin and are more efficient in cisplatin-resistant cell lines. Our results suggest potential utilization of these compounds especially in the treatment of cisplatin-resistant tumor cells.

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Acknowledgments

We would like to thank Dr. Philip J. Coates for critical reading of the manuscript. This work was supported by the project MEYS – NPS I – LO1413, MH CZ-DRO (MMCI, 00209805) and Czech Science Foundation projects P206/12/G151 and P207/12/2368.

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The authors declare no conflict of interest.

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Correspondence to Roman Hrstka.

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Koubkova, L., Vyzula, R., Karban, J. et al. Evaluation of cytotoxic activity of titanocene difluorides and determination of their mechanism of action in ovarian cancer cells. Invest New Drugs 33, 1123–1132 (2015). https://doi.org/10.1007/s10637-015-0274-y

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Keywords

  • Titanocene
  • Cisplatin
  • Ovarian cancer
  • Cytotoxicity
  • Organometallic compounds